Aging leads to increased cellular senescence and is associated with decreased potency of tissue‐specific stem/progenitor cells. Here, we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease, aged 32–86 years. In aged subjects (>70 years old), over half of CPCs are senescent (p16INK4A, SA‐β‐gal, DNA damage γH2AX, telomere length, senescence‐associated secretory phenotype [SASP]), unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs to senescence. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (INK‐ATTAC or wild‐type mice treated with D + Q senolytics) in vivo activates resident CPCs and increased the number of small Ki67‐, EdU‐positive cardiomyocytes. Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and restore the regenerative capacity of the heart. 相似文献
Context: Cluster of differentiation 40 (CD40), and its ligand CD40L, are major co-stimulatory molecules whose interactions are important in both cellular and humoral immunity, and has been suggested to play a role in the pathogenesis of acute coronary syndrome.
Objective: The aim of this study was to examine the association of CD40 polymorphisms (-1?C>T (rs1883832) and 945G>T (rs4810485)) and myocardial infarction (MI), and to test the association of CD40 gene haplotypes with MI in Tunisians.
Materials and methods: Three hundred and fifty MI patients and 301 apparently healthy controls were included in the study. The polymorphisms of CD40 were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
Results: There were significant differences in the genotype and allele frequencies of CD40 gene -1?C>T (rs1883832) polymorphism between cases and controls. Stratifying according to gender, the association between the TT genotype and MI was statistically significant in males, only. Haplotype analysis revealed that the C-T and T-G haplotypes were associated with an increased risk of MI (p?=?0.012 and p?<?0.001, respectively).
Conclusions: Our work showed a significant association between the -1?C>T (rs1883832) polymorphism of the CD40 gene and MI in the Tunisians. 相似文献
According to our previous results, resveratrol (RSV, 3, 5, 4-trihydroxystilbene), a naturally polyphenolic phytoalexin, could attenuate myocardial ischemia/reperfusion injury through up-regulation of vascular endothelial growth factor B (VEGF-B) in isolated rat heart or H9c2 cells. However, the molecular mechanism remains unclear. In this study, we investigated the protective effect of RSV on myocardial infarction (MI) in rats and further explored the underlying signal pathway after VEGF-B. Rats received RSV or normal saline by intragastric administration for 7 consecutive days and followed by subcutaneously isoproterenol (ISO) or normal saline injections for another 2 days. We found that RSV pretreatment prevented the unfavourable changes in HW/BW, HW/TL, infarct size, and cell apoptosis in ISO-treated rats. Moreover, superoxide and malondialdehyde (MDA) production were significantly reduced and superoxide dismutase (SOD) was increased by RSV in ISO-treated rats. Furthermore, it showed that RSV pretreatment increased VEGF-B, p-eNOS and p-AMPK expression, and NO production in ISO-treated rats. Using Neonatal Rat Ventricular Myocytes (NRVM), we found that VEGF-B siRNA could abolish the cardio-protective effect of RSV. The enhanced ratios of eNOS phosphorylation to eNOS expression induced by RSV were markedly reversed by VEGF-B siRNA in NRVM also. Meantime, we found that the effect of VEGF-B knock-down on eNOS activation was rescued by AMPK activator AICAR. L-NAME, a NOS inhibitor, could inhibit RSV enhanced eNOS phosphorylation but had no effect on VEGF-B expression in NRVM or in rats. Collectively, our results indicate that RSV exerts cardio-protection from ISO-induced myocardial infarction through VEGF-B/AMPK/eNOS/NO signalling pathway. 相似文献
Background: There is controversy as to whether older adults with a BMI in the overweight range (25 to 29.9 kg/m2) are at increased health risk and whether they should be encouraged to lose weight. The purpose of this study was to determine whether older adults with a BMI in the overweight range are at increased morbidity and mortality risk. Methods: Participants consisted of 4968 older (≥65 years) men and women from the Cardiovascular Health Study limited access dataset. Based on BMI (kg/m2), participants were grouped into normal‐weight (20 to 24.9 kg/m2), overweight (25 to 29.9 kg/m2), and obese (≥30 kg/m2) categories. Participants were followed for up to 9 years to determine if they developed 10 weight‐related health outcomes that are pertinent to older adults. Cox proportional hazards models were used to estimate the hazards ratios of morbidity and mortality after adjusting for age, sex, income, smoking, and physical activity. Results: Compared with the normal‐weight group, the risks of myocardial infarction, stroke, sleep apnea, urinary incontinence, cancer, and osteoporosis were not different in the overweight group (p > 0.05). The risks for arthritis and physical disability were modestly increased in the overweight group (p < 0.05), whereas the risk for type 2 diabetes was increased by 78% in the overweight group (p < 0.01). After adjusting for all relevant covariates, all‐cause mortality risk was 11% lower in the overweight group (p < 0.05). Conclusions: A BMI in the overweight range was associated with some modest disease risks but a slightly lower overall mortality rate. These findings suggest that a BMI cut‐off point of 25 kg/m2 may be overly restrictive for the elderly. 相似文献